Radionuclide generator and method of sterilization

ABSTRACT

A column assembly of a radionuclide generator includes a column that retains a parent radionuclide that spontaneously decays to a relatively short-lived daughter radionuclide. A fluid path extends from an inlet port to the column and then to an outlet port and allows daughter radionuclide to be eluted from the radionuclide generator for use. Improved retention of parent radionuclide in the column is accomplished by preventing fluid from entering the flow path in a liquid state, such as during sterilization. Proper column chemistry is also promoted by preventing excess moisture from coalescing in the column, which may promote a higher and/or more reliable yield of daughter radionuclide from a radionuclide generator.

BACKGROUND

1. Field

Aspects of the present invention relate to a radionuclide generatorhaving a column assembly that may be terminally sterilized without theintroduction of excess moisture.

2. Discussion of Related Art

Radionuclide generators include a column that has media for retaining along-lived parent radionuclide that spontaneously decays into a daughterradionuclide that has a relatively short-lived life. The column may beincorporated into a column assembly that has a needle-like outlet portthat receives an evacuated vial to draw saline or other eluant liquid,provided to a needle-like inlet port, through a flow path of the columnassembly, including the column itself. This liquid may elute and deliverdaughter radionuclide from the column and to the evacuated vial forsubsequent use in nuclear medical imaging applications, among otheruses. One example of a generator is shown and described in U.S. Pat. No5,109,160, owned by Lantheus Medical Imaging, Inc., and which isincorporated by reference herein in its entirety.

Sterilization to some degree is generally performed on radionuclidegenerators that are used in the medical industry. Sterilization may beperformed by exposing a column assembly of a radionuclide generator,having a column loaded with parent radionuclide, to a saturated steamenvironment. During this process, liquid that resides in the columnassembly, including the column and tubes that extend between the columnand the inlet and outlet ports may be heated to vapor form (e.g., steam)to kill and/or inactivate contaminants. A vent may be included at theoutlet port to allow both the introduction of steam and the release ofvapors from the column during the sterilization process.

As discussed in U.S. Pat. No. 5,109,160, it may be desirable to providea radionuclide generator as a terminally sterile product—that is, aproduct that is sterilized in its final container, or at least that issterilized with the flow path between the inlet port, the column, andthe outlet port assembled in its final form, including any vented ornon-vented vented caps over the inlet and outlet ports. This may becontrasted with aseptic sterilization where at least some of theindividual components that make up the flow path between the inlet port,the column, and the outlet port are sterilized separately andsubsequently assembled together.

SUMMARY

Providing a vented outlet cover at the outlet port of a column assemblyduring sterilization, instead of assembling a cap or cover aftersterilization, may help a product achieve terminal sterilization. Theapplicant has discovered, however, that vented outlet covers may, insome instances, provide an entranceway to the flow path of a columnassembly for unwanted liquid, despite the presence of a filter at thevent opening of a vented outlet cover. In fact, the applicant observedthat a filter on a upwardly facing vent opening has provided a surfaceon which condensate may accumulate during or after steam sterilization.The accumulated condensate was found to breach the filter and enter thecolumn assembly flow path, in some cases, and to be the cause ofreductions in product life (i.e., elution efficiency) and in radioactiveintegrity (i.e., column assemblies emitting an amount of radiation thatexceeds a threshold level), prior to product shipment. These reductions,until the present invention, were unexplained for years.

According to one aspect, a column assembly of a radionuclide generatorincludes a column having an interior containing a medium for retaining along-lived parent radionuclide that produces a relatively short-liveddaughter radionuclide. The column assembly includes an inlet port influid communication with the interior of the column and an outlet portin fluid communication with the interior of the column. The columnassembly includes a vent opening that provides fluid access to theinterior of the column via the outlet port. The vent opening isconfigured to provide fluid access and to prevent condensate fromentering the vent opening or outlet port.

According to another aspect, a method is provided for producing aterminally sterile column assembly of a radionuclide generator. Themethod comprises providing a column assembly of a radionuclide generatorthat includes a column having a long-lived parent radionuclide thatproduces a relatively short-lived daughter radionuclide. The columnassembly also includes an inlet port in fluid communication with thecolumn and an outlet port in fluid communication with the column. Theoutlet port includes a vent opening that provides fluid access to thecolumn. The column assembly is positioned in an orientation with thevent opening facing downwardly to prevent condensate from entering thevent from above. The column assembly is also exposed to steam forsterilization.

According to at least some embodiments, an outlet cover at leastpartially covers the outlet port and includes the vent opening. Theoutlet port may include a needle structure and the outlet cover mayinclude a pierceable membrane that receives the needle structure of theoutlet port. In some embodiments, the outlet cover includes a bodyportion and a removable cap. The vent opening may be defined as anannular space to between the removable cap and the body portion.

According to some embodiments, a filter is in the outlet cover. Thefilter may be bacteria retentive, according to some embodiments. Thefilter may be positioned at the vent opening.

According to some embodiments, a filter may be positioned between and influid communication with the outlet port and the column.

In some embodiments, the inlet port may be accessible from outside of ashielded package that receives the column assembly, when the column isinside of the shielded package. The column assembly may be provided incombination with the shielded package.

A plug may be removably attached to the inlet port to block fluidcommunication to the inlet port from an atmosphere outside of the columnassembly, according to some embodiments.

The medium in the column may include alumina, according to someembodiments.

The column assembly may be provided in combination with the long-livedparent radionuclide and the relatively short-lived daughterradionuclide, according to some embodiments, and the long-lived parentnuclide may include molybdenum-99 and the relatively short-liveddaughter radionuclide may include technetium-99m.

According to some embodiments, a plurality of column assemblies may beexposed to a steam environment at a common time for one or moresterilization cycles. In some embodiments, exposing the plurality ofcolumn assemblies to steam for a single sterilization cycle results inan amount of remaining liquid that varies by 5% or less (relativestandard deviation). In other embodiments, exposing the plurality ofcolumn assemblies to steam for two sterilization cycles results in anamount of remaining liquid that varies by 15% or less (relative standarddeviation).

According to another aspect, a column assembly of a radionuclidegenerator is provided that includes a column and an outlet port. Thecolumn has a medium for retaining a long-lived parent radionuclide thatproduces a relatively short-lived daughter radionuclide. The outlet portis in fluid communication with the column and is covered with a ventedoutlet cover to provide a terminally sterilizable column assembly. Thevented outlet cover has a vent opening that provides fluid access to thecolumn and that prevents the ingress of gravity-driven liquid(condensate) to produce a column assembly that consistently exhibitshigh yield and that prevents migration of parent radionuclide away fromthe column.

According to another aspect, a column assembly of a radionuclidegenerator includes a column and an outlet port. The column has a mediumfor retaining a long-lived parent radionuclide that produces arelatively short-lived daughter radionuclide. The outlet port is influid communication with the column and is covered with a vented outletcover to provide a terminally sterilizable column assembly. Means areprovided to prevent the ingress of gravity-driven liquid to produce acolumn assembly that consistently exhibits high yield and that preventsmigration of parent radionuclide away from the column.

According to some embodiments, the means comprises a vent opening thatprovides fluid access to the column and that prevents the ingress ofgravity-driven liquid. The vent opening may face toward the column,according to some embodiments.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings are not intended to be drawn to scale. In thedrawings, each identical or nearly identical component that isillustrated in various figures is represented by a like numeral. Forpurposes of clarity, not every component may be labeled in everydrawing. In the drawings:

FIG. 1 is a cross sectional view of a column assembly, according to oneembodiment, that includes a flow path extending from an inlet portcovered with a plug, through a column, and to an outlet port coveredwith an outlet cover having a vent configured to prevent the ingress ofliquid.

FIG. 2 shows portions of the column assembly of FIG. 1, configured forcharging of the column with parent radionuclide.

FIG. 3 is a cross sectional view of a vented outlet cover with a ventopening oriented to prevent the ingress of liquid from above, accordingto one embodiment.

FIG. 4 is a cross sectional view of the column assembly shown in FIG. 1,assembled into a shielded package.

FIG. 5 shows elution efficiencies for column assemblies having a ventedoutlet cover with a vent that opens upwardly, and that exceeded an upperthreshold limit for emitted radiation.

FIGS. 6A and 6B show column assembly residual moisture levels recoveredfrom column assemblies that were found to exceed an upper thresholdlimit for emitted radiation and for column assemblies that did notexceed the upper threshold limit for is emitted radiation.

FIG. 7 shows change in column assembly weights during steamsterilization for column assemblies having vent openings orientedupwardly.

FIG. 8 shows change in column assembly weights during sterilization forcolumn assemblies having vent openings oriented to prevent the ingressof liquid.

FIG. 9 shows change in column assembly weights during two consecutivesteam sterilizations for column assemblies having vent openings orientedupwardly.

FIG. 10 shows change in column assembly weights during two consecutivesteam sterilizations for column assemblies having vent openings orientedto prevent the ingress of liquid.

DETAILED DESCRIPTION

Broadly speaking, a radionuclide generator includes a column thatretains a parent radionuclide which spontaneously decays to a relativelyshort-lived daughter radionuclide. The column may be incorporated into acolumn assembly that includes a fluid path extending from an inlet port,through the column, and then to an outlet port from which daughterradionuclide may be delivered for use. The column assembly is typicallypositioned within a shielded package. Some aspects described hereinprovide for improved retention of parent radionuclide in the columnwhere radioactive shielding is typically the greatest. This may beaccomplished by venting a column assembly in a manner that prevents theingress of liquids during sterilization, yet that allows for theexchange of steam and/or other vapors. This, in turn, may reliablyprevent excess liquid from being introduced to portions of the columnassembly, such as portions of the inlet and outlet tubes where thepresence of excess liquid might provide a pathway for unwanted migrationof radionuclide. Other aspects of the invention relate to reliablypreventing excess moisture from coalescing in or about the column, whichmay adversely impact column chemistry and lead to reduced yield ofdaughter radionuclide.

Parent radionuclide is typically provided to a column in a fluid charge,where the radionuclide selectively binds to media in the column whilethe fluid charge is drawn through the column along a flow path of acolumn assembly. During sterilization there is an exchange of vapors,through the vented outlet cover, between heated, residual charging fluidresiding in the column assembly flow path and the saturated steampresent in a sterilization chamber. During the cooling process thatfollows sterilization, steam may condense about a column assembly andmay enter the column assembly, as liquid, through an outlet port (absentfeatures to prevent the ingress of gravity-driven liquid), resulting inexcess liquid in the column assembly flow path. Excess liquid that mayreside in the column or other portions of the flow path between theinlet port and outlet port of a radionuclide generator column assemblymay provide a path along which parent radionuclide may migrate.Migration, in some instances, may occur to areas of a flow path that areshielded to a lesser degree than the column itself, which may result inradiation being emitted at a level that exceeds a threshold level.Aspects of the invention described herein relate to controlling themoisture content of a column assembly during and/or after steamsterilization so as to prevent excess liquid in the flow path of acolumn assembly, along which radionuclide may migrate.

Excess moisture in the column or column assembly of a radionuclidegenerator may result from the entry of liquid into the column assemblyduring or after steam sterilization, and may adversely impact columnchemistry, resulting in reduced yield of daughter radionuclide. Aspectsof the invention relate to controlling the amount and/or phase state ofmoisture that may enter a column during or after sterilization topromote the production of a high yield radionuclide generator.

It many instances, it may be desirable to provide a radionuclidegenerator that is terminally sterile. This involves sterilizing thecolumn assembly, including the flow path between inlet port, column, andthe outlet port, and any plugs or vented covers positioned on the inletand outlet ports, when assembled together in final form, at least priorto being installed in a shielded container. Aspects of the inventionrelate to providing a terminally sterile product, includingsterilization after fully assembling any plugs and vented covers to theflow path, while also reliably controlling the amount of moisture in theflow path of the column assembly.

Turning now to the Figures, and initially FIG. 1, one embodiment of acolumn assembly 10 of a radionuclide generator is shown. The columnassembly 10 includes a column 12 having a media 13 and that is fluidlyconnected at one end to an inlet port 14 and a charge port 16 through aninlet line 18 and a charge line 20, respectively. As shown, the inletport 14 and charge port 16 are each covered with a plug 22, 24. A ventport 26 that communications fluidly with an eluant vent 28 is positionedadjacent to the inlet port 14, and may, in operation, provide a vent toa vial or bottle of eluant connected to the inlet port, as described ingreater detail herein.

The column assembly 10 also includes an outlet port 30 that is fluidlyconnected to the bottom of the column 12 through an outlet line 32. Afilter assembly 34 is incorporated into the outlet line, and the outletport 30 is covered with a vented outlet cover 36 that also includes afilter, as described in greater detail below. Various aspects of theillustrated embodiment of the column assembly are described in greaterdetail in U.S. Pat. No 5,109,610 (Evers), owned by Lantheus MedicalImaging, Inc, which is hereby incorporated by reference in its entirety.Additionally, column construction materials and operation are describedin U.S. Pat. No. 3,476,998 (Deutsch) and U.S. Pat. No. 3,774,035 (Litt),each of which is also hereby incorporated by reference in its entirety.

Manufacture of a radionuclide generator, according to some embodiments,includes charging the column with a parent radionuclide after the columnassembly has been assembled. This may be accomplished by providing avial or bottle that includes a parent radionuclide, such asmolybdenum-99 (Mo-99) in solution, to the charge port 16. The Mo-99 insolution is then drawn to the column, either by applying a vacuum at theoutlet port 30 or by driving the fluid to the column under pressureprovided at the charge port 16. The parent radionuclide in solutionpasses through a medium 13 in the column, such as alumina, that has anaffinity for and that retains parent radionuclide therein. It is to beappreciated that embodiments of the column assembly may be charged withparent radionuclide other than molybdenum-99 (which producestechnetium-99m as a daughter radionuclide). By way of non-limitingexample, column assemblies may be charged with germanuim-68 as a parentradionuclide to produce gallium-68 as a daughter radionuclide or withtungsten-188 as a parent radionuclide to produce rhenium-188 as adaughter radionuclide.

FIG. 2 illustrates portions of a column assembly configured for chargingthe column with parent radionuclide. Having a charge line 20 and chargeport 16 that are separate from the inlet line 18 and inlet port 14 (asshown in FIG. 1), which are typically plugged as the column 12 ischarged, may prevent radionuclide from entering the inlet line 18 of thecolumn assembly 10. A plug 24, which may be permanent, may be placedover the charge port 16 after charging the column to prevent migrationof radionuclide back up the charge line 20 from the column. Aftercharging, a vented outlet cover 36 may be positioned over the outletport 30 (as shown in FIG. 1). Other plugs and features, including a ventcap 38 positioned over the eluant vent 28, may be assembled to thecolumn assembly 10 prior to or after charging the column to ready thedevice for sterilization.

The flow path of the column assembly 10, including the inlet port 14,inlet line 18, column 12, outlet line 32, and outlet port 30, amongother features, may be sterilized with the inlet plug 22 and ventedoutlet cover 36 in position, and prior to the column assembly beingplaced in a shielded package 40 (as shown in FIG. 4). Sterilization ofthe column assembly in this manner may provide for a terminally sterilecolumn assembly, given that no further manipulations of customer accesspoints (i.e., the inlet port and the outlet port) or internal portionsof the flow path therebetween may be performed subsequent tosterilization and prior to the radionuclide generator being accessed byan end user. Alternatively, the column assembly may merely be assembledinto a shielded package to complete assembly of a radionuclidegenerator, as discussed in greater detail herein, and readied forshipment.

According to some embodiments, sterilization includes exposing thecolumn assembly 10 to a saturated steam environment. This may involveplacing one or more column assemblies into a sterilization chamber, eachassembly having a plug 22 positioned over the inlet port and optionallyover the vent port 26, and a vented outlet cover 36 positioned over theoutlet port 30. Steam is provided to the sterilization chamber as thepressure of the chamber is increased until a desired temperature andpressure are achieved. According to some embodiments, column assembliesare exposed to a saturated steam environment at a pressure higher thanatmospheric. It is to be appreciated that sterilization may involvevarious combinations of temperature and pressure values, such ascombinations of pressure and temperature associated with a saturatedsteam environment, as may be determined from a psychrometric chart, andthat types of sterilization other than saturated steam may also be used,as the embodiments are not limited to the sterilization techniquesdescribed herein. Additionally, different combinations of plugs and/orvented covers may be positioned over the inlet, outlet, and/or otheraccess points, and in some embodiments, access points may be uncoveredduring sterilization,

A column assembly may be oriented during sterilization to help retainradionuclide activity within the column and/or portions of the flow pathnear the column. According to some embodiments, the column assembly 10may be oriented in a similar way, typically with the column assemblylower than other portions of the flow path, both during sterilizationand when placed in a shielded package 40 for delivery and/or use Asshown in the embodiment of FIG. I, the column 12 may be positioned neara lower portion of a column assembly 10, such that any liquid within thesystem is directed by gravity toward the column or portions of the flowpath that are near the column, where shielding of a shielded package isgenerally thicker. The inlet and outlet lines 18, 32 may be orientedsubstantially vertically or diagonally downward at all points, lackingdips or horizontal sections that might otherwise trap liquid containingradionuclide after charging, elution, and/or during sterilization. It isto be appreciated that the embodiment of FIG. 1 shows but oneconfiguration of inlet and outlet lines, and other others are alsopossible, including for instance lines that are configured differentlyfrom that shown in FIG. 1, but that are generally ramped downward towardan area near the column at all points along their length.

During steam sterilization, residual fluid used in charging the columnwith radionuclide is heated to a vapor form (e.g., steam) to kill and/orinactivate contaminants. The vapor may be driven at least partially fromthe column assembly while steam also enters the column assembly from thesaturated steam environment within the sterilization chamber, such thatthere may be minimal or no net change in moisture content of a columnassembly during sterilization. At least one vent opening, typicallypositioned at the outlet port, and that may optionally include a filter,may be left open between the column and the steam environment during thesterilization process to allow for the ingress and egress of steam tothe column. Although moisture exchange occurs between the flow path ofthe column assembly, including the column itself, and the environmentduring sterilization, no net change or a minimal net change in theamount of moisture in the column assembly may generally be desirable.

Condensation may occur as the environment about the column assemblycools to room temperature and/or returns to atmospheric pressure aftersterilization. Such condensation may collect on surfaces of the columnassembly, and particularly horizontal surfaces, such as the top 42 ofthe vented outlet cover 36 (or equivalently the filter 37 of ventedoutlet cover 36, absent cap 48 and top surface 42 as shown in FIG. 3).Additionally or alternatively, particular positions within asterilization chamber may be more prone to the production ofcondensation, due to air flow within the chamber, or by virtue of beingpositioned under features from which condensate may drip, among otherfactors. The applicant has appreciated that while the flow of saturatedsteam both to and from the flow path of a column assembly may provebeneficial in the sterilization process, that the introduction of fluidin a liquid state, such as condensate, to the flow path during or aftersterilization may not be desirable. Steam or fluid in vapor form maynaturally flow to and from the flow path of a column assembly atequivalent rates and/or equivalent amounts, such that there is minimalor no net change in moisture content of a column assembly duringsterilization. On the other hand, fluid that may enter the flow path ofa column in liquid form, particularly after the sterilization process,may not find a way back to the external environment, resulting in a netgain of moisture content in a column assembly subsequent tosterilization.

Embodiments of the vented outlet cover 36 may include one or morefeatures to prevent the ingress of fluid in liquid form, while allowing,the ingress and egress of fluid in a vapor form (e.g., steam). In oneillustrative embodiment shown in FIG. 3, the cover 36 includes a ventopening 44 that faces substantially downwardly, such that condensate,when driven by gravity, will not enter the vent opening 44, but insteadbe shed downward toward lower, external portions of the column assemblyor away from the column assembly 10 altogether. It is to be appreciatedthat the term “downwardly” as used herein with respect to a columnassembly refers to a direction in which the pull of gravity draws a massin relation to a column assembly that is oriented for use. In theillustrated embodiment, the vent opening 44 has an annular shape that isdefined between a body portion 46 of the cover and a removable cap 48positioned on the body portion. The cap 48 includes a liquid impermeabletop surface 42 that is positioned above the vent opening 44, whenassembled, and prevents water from entering the vent from above.Components of the vented outlet cover represented by FIG. 3 may beacquired from Filtertek, Inc. of Hebron, IL. It is to be appreciatedthat FIG. 3 shows one embodiment of a vented outlet cover, and thatother embodiments are also possible. By way of example, the ventedoutlet cover may include a vent opening that is oriented to preventwater from entering the vent without the vent opening facing directlydownward. According to some embodiments, the vent opening may beoriented to face substantially sideways and still prevent liquid fromentering the vent opening, and the flow pathway of a column assembly. Itis to be appreciated that the term “vent opening” or equivalently“vent”, as used herein, refers to a space or opening delimited byportions of the column assembly and through which steam may pass from anenvironment external to the column assembly, through the outlet port,and into the interior of a column assembly.

Whether an upward facing vent opening, of a column assembly is exposedto liquid during sterilization may be a result of the column assemblybeing positioned in particular places within a sterilizer and/or bychance, as one of skill in the art is to appreciate. In this respect, itis possible that column assemblies with upwardly facing vent openingsmay be sterilized without the introduction of excess liquid. Theintroduction of liquid to such column assemblies, however, may prove tobe unpredictable. In contrast, column assemblies having vent openingsfacing downwardly may prevent or reduce the introduction of liquidand/or excessive moisture into the column. According to someembodiments, the liquid content amongst a plurality of columnassemblies, after a single sterilization cycle, may vary as measured instandard deviation by fewer than 0.015 grams, fewer than 0.010 grams,fewer than 0.005 grams, or by an even lesser amount. According to someembodiments, column assemblies with an average of 0.040 grams of liquidmay vary in liquid content by 0.002 grams or fewer (standard deviation)after a single sterilization cycle. Similarly, the liquid content mayvary by less than 40%, less than 30%, less than 20%, less than 10%, lessthan 5%, less than 4%, less than 3%, less than 2%, or even less than 1%,as measured in relative standard deviation, after a single sterilizationcycle. These reductions in standard deviation and relative standarddeviation may represent greater than a 25% reduction, a 50% reduction, a75% reduction, or even greater than a 90% reduction as compared tocolumn assemblies that lack vent openings that face downwardly (e.g.,that have vent openings facing upwardly). The liquid content amongst thesame plurality of column assemblies, after a second sterilization cycle,may vary as measured in standard deviation by fewer than 0.100 grams,fewer than 0.050 grams, fewer than 0.010 grams, or by an even lesseramount. In some embodiments, column assemblies with an average of 0.039grams of liquid may vary in liquid content by 0.006 grams or fewer(standard deviation) after two sterilization cycles. Similarly, theliquid content may vary by less than 200%, less than 100%, less than50%, less than 15%, less than 10%, less than 5%, less than 4%, less than3%, less than 2%, or even less than 1%, as measured in relative standarddeviation, after two sterilization cycles. These reductions in standarddeviation and relative standard deviation may represent greater than a25% reduction, a 50% reduction, a 75% reduction, or even greater than a90% reduction as compared to column assemblies that lack vent openingsthat face downwardly (e.g., that have vent openings facing upwardly).

The cap 48 of the vented outlet cover shown in FIG. 3 is configured tobe removable from the body portion 46 of the vented outlet cover. Asshown, the cap 48 includes tabs 35 that mate with corresponding featuresof the body portion 46 to hold the cap in place. Removable caps may beconfigured to mate to other portions of the vented outlet cover in otherways, such as with threaded connections, press fit connections, and thelike, according to some embodiments. According to other embodiments, thevented outlet cover may lack a removable cap while still having a ventopening that faces substantially downward.

The outlet port, according to some embodiments, may additionally oralternatively be configured to prevent the ingress of gravity-drivenliquid, such as condensate, when a column assembly is oriented with acolumn positioned lower than the outlet port for sterilization,shipment, and/or use. By way of example, according to some embodiments,the outlet port itself may act as a vent opening and face substantiallydownwardly, such that gravity-driven liquid may not enter the ventopening from above. Such embodiments may be sterilized without a ventedoutlet cover assembled to the column assembly, and may additionally beshipped for use without a vented outlet cover.

The vented outlet cover 36 may connect to the outlet port 30 indifferent manners. In the embodiment of FIG. I, the outlet port 30includes a needle-like structure, and the vented outlet cover 36includes a pierceable membrane 50 (as shown in FIG. 3) that may receivethe needle-like structure to provide a seal therebetween and to retainthe outlet cover in place. Other types of connections, however, are alsopossible, including screw type connections and/or press type fitconnections, to name a few.

Filters may be incorporated into the flow path of a column assembly,according to some embodiments. The embodiment of FIG. 1 includes afilter 34 assembly positioned in the outlet line 32 to prevent theegress of particulates from the column and to maintain sterility of theradionuclide generator eluate. Similar filters may additionally oralternatively be positioned elsewhere in the flow path of a columnassembly. For example, a filter 37 may be positioned within a ventedoutlet cover 36, as shown in FIG. 3, or even directly at the opening ofthe vent, according to some embodiments. The filter may include a glassmatrix sandwiched between cellulose layers that hold the glass matrix inplace, and may be configured to retain bacteria, rather than solelypreventing bacteria passage.

The column assembly 10 may be positioned in a package 40 that includesshielding to prevent the emission of radiation from the column assemblyabove a threshold value. By way of example, FIG. 4 shows the columnassembly 10 of FIG. 1 assembled into a package 40 that has a lead shieldbase 54 or shield of other suitable material, such as tungsten ordepleted uranium, held in position by a spacer 56. The package receivesthe column assembly with a column shield 58 positioned around the column12 and a shield plug 60 positioned about portions of the inlet andoutlet lines of the flow path. As may be appreciated, the thickest andthus greatest amount of shielding may typically exist around the column12, where radionuclide is expected to reside. The inlet and outlet lines18, 32 are also shielded, but to a lesser degree. The package 40additionally includes a charge well 62 about the inlet port 14 and thevent port 26 where an eluant bottle may be received when daughterradionuclide are to be eluted. The package may also include a collectionwell 64 about the outlet port 30 that may be accessed by a shielded,evacuated vial or other container when radionuclide are retrieved fromthe column assembly 10, as discussed in greater detail herein. A dustcover 66 may be removably positioned over the charge well 62 andcollection well 64, and the package may include a handle 68, as shown inFIG. 4.

Embodiments of column assemblies may be configured to prevent radiationemission from exceeding different threshold levels, according to varyingcriteria. By way of non-limiting example, according to some embodiments,a common threshold level may be defined for column assemblies,regardless of a charge level, as measured in Curies, of a radionuclidegenerator. According to one embodiment, a threshold limit of 200 mR/hrmay be set as a threshold limit, as measured outside of a squarecorrugated carton having side edges of about 14″ in length and thatencloses a column assembly positioned inside of a shielded package.Other values of threshold limits may alternatively be set, such as atlower threshold limits as the embodiments described herein are notlimited to any one threshold value. According to other embodiments,threshold limits may depend on the degree to which a column assembly ischarged with parent radionuclide. Some examples of threshold levelsassociated with different charge levels, are shown below in Table 1.

TABLE 1 Examples of Threshold Limits Charge Level (mCi) Threshold Limit(mR/hr) 1000 27 2000 41 2500 46 3000 36 4000 46 4500 50 5000 54 6000 637500 76 10000 98 12500 121 15000 140 18000 159

To retrieve daughter radionuclide from the generator, the dust cover 66is first removed, and then the inlet port plug 22 is removed from theinlet port 14 and vent port 26. The vented outlet cover 36 is alsoremoved from the outlet port 30. A bottle (not shown) including eluant,such as saline, is then placed in fluid communication with the inletport 14 and vent port 26. As shown, the vent port 26 and inlet port 14may comprise needles that puncture and then seal against a diaphragm ofthe bottle, although other connections are also possible as embodimentsare not limited to that which is illustrated in the figures. A shielded,evacuated collection vial (not shown), having a connection similar tothat of the eluant bottle, is then connected to the outlet port 30. Thenegative pressure of the evacuated vial draws eluant from the eluantbottle and through the flow pathway, including the column, to elutedaughter radionuclide for delivery through the outlet port and to theshielded, evacuated vial. The vent allows air to enter the eluant bottlethrough the vent port to prevent negative pressure in the eluant bottlethat might otherwise impede the flow of eluant through the flow pathway.After having eluted daughter radionuclide from the column, the shielded,evacuated collection vial is removed from the outlet port of thegenerator, and a vial containing a preservative (not shown), having aconnection similar to that of the eluant bottle and collection vial isinserted onto the outlet port. The radionuclide generator may then bestored until radionuclide is again to be eluted.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the invention. The advantages and objects of the inventionare not necessarily encompassed by each embodiment of the invention.

The present invention is further illustrated by the following Examples,which in no way should be construed as further limiting.

EXAMPLES Example 1 Elution Efficiency Results of Column AssembliesExceeding Threshold Limits

Production of column assemblies configured as shown in FIG. 1, but witha vented outlet cover having a vent that opens upwardly rather thandownwardly (e.g., a column assembly like that of FIG. 1 but with the cap48 removed), was monitored to identify column assemblies that exceededan upper threshold radiation limit, as may be associated with a parentradionuclide present in an outlet or inlet line. Radionuclide was elutedfrom the column assemblies that exceeded the upper threshold limit.Elution efficiency (Tc-99m yield) was then measured for these columnassemblies. For some of the column assemblies, residual moisture levelswere tested prior to measuring elution efficiency, while for others,elution efficiency was measured, without testing residual moisturelevels.

The elution efficiency results for all column assemblies are shown inFIG. 5. The elution efficiency is the ratio of the actual yield ofdaughter radionuclide to the expected yield of daughter radionuclide,corrected for the elapsed time between elutions. Typically, the Tc-99melution efficiency is 85%-95%. The Tc-99m yield for the columnassemblies that exceeded a threshold limit was impacted forapproximately 80% of the column assemblies that were tested for elutionefficiency, with 58% of the column assemblies tested exhibiting lessthan 10% elution efficiency. For comparison, five non-high dose columnassemblies (#1815-181B) are also shown in FIG. 5, and have elutionefficiency values that exceed 85%. The results of this example suggest acorrelation between exceeding upper threshold radiation limits andexhibiting elution efficiency less than 85%.

Example 2 Residual Moisture Recovered from High Dose and Non-High DoseColumn Assemblies

Production of column assemblies configured as shown in FIG. 1, but witha vented outlet cover having a vent that opens upwardly rather thandownwardly (e.g., a column assembly like that of FIG. 1, but with thecap 48 removed), was monitored to identify column assemblies thatexceeded an upper threshold radiation limit, as may be associated with aparent radionuclide present in an outlet or inlet line. Columnassemblies that exceeded the upper threshold limit were checked forresidual moisture, as were column assemblies that did not exceed theupper threshold limit. Residual moisture was measured using an evacuatedvial connected to the outlet port to recover moisture from the fluidpath between the inlet port and outlet port, including the column.

The results, shown in FIGS. 6 a and 6 b, show that column assembliesfound to exceed the upper threshold limit consistently exhibitedmoisture levels at or in excess of 0.5 grams, while column assembliesthat did not exceed the upper limit exhibited moisture levels typicallyless than 0.05 grams. These results suggest that increased residualmoisture in the column assembly may promote the movement of radionuclideto to less shielded areas of a column assembly, including the outletline and/or inlet line, which may result in a column assembly exceedingan upper threshold limit for radiation. Furthermore, excess moisture mayreduce elution efficiency (Tc-99m yield) as discussed in Example 1.

Example 3 Weight Change and Recovered Liquid for Column AssembliesHaving

Vents Oriented Upwardly and Having Vents Oriented Downwardly

Positions were identified within a steam sterilizer where columnassemblies having vents oriented upwardly were previously found to haverelatively wide range of residual moisture levels followingsterilization. Column assemblies configured as shown in FIG. 1, but witha vented outlet cover having a vent that opens upwardly rather thandownwardly (e.g., a column assembly like that of FIG. 1, but with thecap 48 removed), were charged with eluant lacking radionuclide. Columnassemblies were charged with different amounts of eluant so as torepresent different size (i.e., Mo-99 activity levels) of radionuclidegenerators that are typically produced. The column assemblies wereweighed, and placed in the identified positions within the sterilizerfor steam sterilization. The column assemblies were subjected to steamsterilization, and then again weighed after sterilization. A change incolumn assembly weight was calculated. Results of this test are shown inFIG. 7.

The test was then repeated with column assemblies configured as shown inFIG. 1, including a vented outlet cover with a vent that opensdownwardly. The results of this test are shown in FIG. 8. The meanrecovered liquid from the column assemblies having vents that opendownwardly was 0.040 grams, a 25% reduction from the 0.053 grams of thecolumn assemblies having vents that open upwardly. Additionally, thestandard deviation of liquid recovered from column assemblies havingvents that open downwardly was 0.002 grams, as opposed to 0.024 gramsfor column assemblies having vents that open upwardly. Similarly, therelative standard deviation of liquid recovered from column assemblieshaving vents that open downwardly was 5.0%, as opposed to 45.3% forcolumn assemblies having vents that open upwardly, a reduction of 90.0%.

Example 4 Weight Change and Recovered Liquid for Column AssembliesHaving Vents Oriented Upwardly and Having Vents Oriented DownwardlyAfter Two Sterilizations

The procedures described above with respect to Example 3 were repeated,except that column assemblies were subjected to two complete steamsterilizations, as may occur in the production of radionuclidegenerators when a steam sterilization is interrupted, such as due to apower outage, and may need to be repeated. The results for columnassemblies configured as shown in FIG. 1, but with a vented outlet coverhaving a vent that opens upwardly rather than downwardly, are shown inFIG. 9. The results for column assemblies configured as shown in FIG. 1,including a vented outlet cover with a vent that opens downwardly, areshown in FIG. 10. The mean recovered liquid from the column assemblieshaving vents that open downwardly was 0.039 grams, a 64% reduction fromthe 0.108 grams of the column assemblies having vents that openupwardly. Additionally, the standard deviation of liquid recovered fromcolumn assemblies having vents that open downwardly was 0.006 grams, asopposed to 0.231 grams for column assemblies having vents that openupwardly. Similarly, the relative standard deviation of liquid recoveredfrom column assemblies having vents that open downwardly was 15.4%, asopposed to 214.0% for column assemblies having vents that open upwardly,a reduction of 92.8%.

This Example suggests that a vented outlet cover with a vent that opensdownwardly may prevent the ingress of excess liquid, even after multiplesteam sterilizations.

Having thus described several aspects of at least one embodiment of thisinvention, it is to be appreciated various alterations, modifications,and improvements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

What is claimed is: 1-16. (canceled)
 17. A method of producing aterminally sterile column assembly of a radionuclide generator,comprising: providing a column assembly of a radionuclide generator thatincludes: a column having a long-lived parent radionuclide that producesa relatively short-lived daughter radionuclide; an inlet port in fluidcommunication with the column; and an outlet port in fluid communicationwith the column, the outlet port includes a vent opening that providesfluid access to the column; positioning the column assembly in anorientation with the vent opening facing downwardly to preventcondensate from entering the vent opening from above; exposing thecolumn assembly to steam for sterilization; and positioning an outletcover over the outlet port prior to exposing the column assembly tosteam for sterilization, the outlet port including the vent opening. 18.The method of claim 17, wherein positioning the outlet cover over theoutlet port includes positioning an outlet cover that includes aremovable cap.
 19. A method of producing a terminally sterile columnassembly of a radionuclide generator, comprising: providing a columnassembly of a radionuclide generator that includes: a column having along-lived parent radionuclide that produces a relatively short-liveddaughter radionuclide; an inlet port in fluid communication with thecolumn; and an outlet port in fluid communication with the column, theoutlet port includes a vent opening that provides fluid access to thecolumn; positioning the column assembly in an orientation with the ventopening facing downwardly to prevent condensate from entering the ventopening from above; exposing the column assembly to steam forsterilization; and plugging the inlet port of the column assembly priorto exposing the column assembly to steam for sterilization.
 20. A methodof producing a terminally sterile column assembly of a radionuclidegenerator, comprising: providing a column assembly of a radionuclidegenerator that includes: a column having a long-lived parentradionuclide that produces a relatively short-lived daughterradionuclide; an inlet port in fluid communication with the column; andan outlet port in fluid communication with the column, the outlet portincludes a vent opening that provides fluid access to the column;positioning the column assembly in an orientation with the vent openingfacing downwardly to prevent condensate from entering the vent openingfrom above; and exposing the column assembly to steam for sterilization;wherein exposing the column assembly to steam includes exposing thecolumn assembly to saturated steam under pressure.
 21. A method ofproducing a terminally sterile column assembly of a radionuclidegenerator, comprising: providing a column assembly of a radionuclidegenerator that includes: a column having a long-lived parentradionuclide that produces a relatively short-lived daughterradionuclide; an inlet port in fluid communication with the column; andan outlet port in fluid communication with the column, the outlet portincludes a vent opening that provides fluid access to the column;positioning the column assembly in an orientation with the vent openingfacing downwardly to prevent condensate from entering the vent openingfrom above; and exposing the column assembly to steam for sterilization;wherein providing the column assembly comprises providing a plurality ofcolumn assemblies and wherein positioning the column assembly andexposing the column assembly comprise positioning the plurality ofcolumn assemblies and exposing the plurality of column assemblies,respectively.
 22. The method of claim 21, wherein exposing the pluralityof column assemblies to steam for a single sterilization cycle resultsin an amount of liquid remaining in the plurality of column assembliesthat varies by 5% or less (relative standard deviation).
 23. The methodof claim 21, wherein exposing the plurality of column assemblies tosteam for two sterilization cycles results in an amount of liquidremaining in the plurality of column assemblies that varies by 15% orless (relative standard deviation).
 24. (canceled)
 25. A column assemblyof a radionuclide generator, comprising: a column and an outlet port,the column including a medium for retaining a long-lived parentradionuclide that produces a relatively short-lived daughterradionuclide, the outlet port in fluid communication with the column andcovered with a vented outlet cover to provide a terminally sterilizablecolumn assembly, the vented outlet cover having a vent opening thatprovides fluid access to the column and that prevents the ingress ofgravity-driven liquid to produce a column assembly that consistentlyexhibits high yield, wherein the outlet port includes a needle structureand the vented outlet cover includes a pierceable membrane that receivesthe needle structure of the outlet port.
 26. The column assembly ofclaim 25, wherein the outlet cover includes a body portion and aremovable cap.
 27. The column assembly of claim 26, wherein the ventopening is defined as an annular space between the removable cap and thebody portion.
 28. The column assembly of claim 27, further comprising: abacteria retentive filter in the body portion.
 29. (canceled)
 30. Acolumn assembly of a radionuclide generator, comprising: a column and anoutlet port, the column including a medium for retaining a long-livedparent radionuclide that produces a relatively short-lived daughterradionuclide, the outlet port in fluid communication with the column andcovered with a vented outlet cover to provide a terminally sterilizablecolumn assembly, wherein means are provided to prevent the ingress ofgravity-driven liquid to produce a column assembly that consistentlyexhibits high yield and that prevents migration of parent radionuclideaway from the column, wherein the outlet port includes a needlestructure and the vented outlet cover includes a pierceable membranethat receives the needle structure of the outlet port.
 31. A columnassembly of a radionuclide generator, comprising: a column and an outletport, the column including a medium for retaining a long-lived parentradionuclide that produces a relatively short-lived daughterradionuclide, the outlet port in fluid communication with the column andcovered with a vented outlet cover to provide a terminally sterilizablecolumn assembly, wherein means are provided to prevent the ingress ofgravity-driven liquid to produce a column assembly that consistentlyexhibits high yield and that prevents migration of parent radionuclideaway from the column, wherein the means comprises a vent opening thatprovides fluid access to the column and that prevents the ingress ofgravity-driven liquid.
 32. The column assembly of claim 31, wherein thevent opening faces toward the column.
 33. The column assembly of claim31, wherein the outlet cover includes a body portion and a removablecap.
 34. The column assembly of claim 31, wherein the vent opening isdefined as an annular space between the removable cap and the bodyportion. 35-36. (canceled)
 37. A column assembly of a radionuclidegenerator, comprising: a column and an outlet port, the column includinga medium for retaining a long-lived parent radionuclide that produces arelatively short-lived daughter radionuclide, the outlet port in fluidcommunication with the column and covered with a vented outlet cover toprovide a terminally sterilizable column assembly, the vented outletcover having a vent opening that provides fluid access to the column andthat prevents the ingress of gravity-driven liquid to produce a columnassembly that prevents migration of parent radionuclide away from thecolumn wherein the outlet port includes a needle structure and thevented outlet cover includes a pierceable membrane that receives theneedle structure of the outlet port.
 38. The column assembly of claim37, wherein the outlet cover includes a body portion and a removablecap.
 39. The column assembly of claim 38, wherein the vent opening isdefined as an annular space between the removable cap and the bodyportion.
 40. The column assembly of claim 39, further comprising: abacteria retentive filter in the body portion.